Type 2 diabetic bone fragility: the effects of a high-fat, - cholesterol, and -sucrose diet, exercise, and caloric restriction

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] As the prevalence of type 2 diabetes (T2D) continues to increases, new comorbidities associated with the condition as discovered. A recently recognized comorbidity of T2D is an ~1.7-fold increased risk of fracture. To date the underlying mechanisms responsible for the deterioration in bone quality have not been fully elucidated. A current mechanism of interest is the regulation of mesenchymal stem cell differentiation. Specifically, if T2D suppresses osteoblastogenesis is due to an impairment in Wnt/ß-catenin signaling resulting in a reduction in the expression of runtrelated transcription factor 2 (Runx2). In this work we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, to determine that a high-fat, -sucrose, -cholesterol (HFC) diet did not detrimentally impact bone outcomes, and that the development of obesity/T2D negatively impacted serum bone turnover markers and trabecular microarchitecture. From a clinical perspective, these data are relevant because we have shown that an imbalance in energy intake, resulting in the development of obesity/T2D has a negative impact on bone outcomes independent of the macronutrient composition of the diet. An additional area of focus of this work was determining if the beneficial effects of EX on bone health in the OLETF rat were due to an improvement in metabolic health or the unique effects of exercise. Because EX interventions improve metabolic health, a weight-matched control is necessary to differentiate the effects of improved metabolic health from additional beneficial effects of EX (i.e., mechanical loading, endocrine/paracrine changes). From this study were able to determine that EX or CR generally improved bone outcomes, EX treatment resulted in several unique benefits including an increase in femora periosteal expansion, mass accumulation, and increased whole-bone stiffness. EX or CR prevented the marked increase in bone resorption observed in obese, T2D OLETF rats, and either EX or CR reduced circulating OC. Likewise, EX or CR increased tissue-level bone strength and stiffness, but EX had a greater positive effect on tissue-level strength. Thus, it appears that the skeletal benefits of EX result from both improved metabolic health and exercise-specific effects. Few studies have investigated the effects of exercise on bone health after insulin resistance and/or T2D is already present. Determining if EX (initiated after the onset of insulin resistances) is an effective strategy for combating T2D-associated bone fragility is highly relevant from a clinical treatment perspective because treatment of T2D often occurs after the onset of insulin resistance/T2D. EX or CR treatment initiated after the onset of insulin resistance improved metabolic health, and in general improved bone health. However, EX elicited additional benefits to bone outcomes. Specifically, EX or CR preserved trabecular bone volume and structure, while cortical whole-bone and tissuelevel strength were only improved with EX in OLETF rats. These improvements in bone health by EX were associated with an increase in expression of the osteoblastogenic transcription factor Runx2 and a reduction in the adipogenic transcription factor PPAR?. These findings are clinically relevant because in humans treatment occurs after the onset of insulin resistance or T2D. Our data suggest that EX is not only an effective treatment for T2D, but EX has a greater beneficial effect on bone health than CR given similar improvements in glucose control.